Process for the preparation of pharmaceutical microcapsules with enhanced taste-masking and high dissolution rate

ABSTRACT

Process for the production of microcapsules containing a drug and comprising a layer of ethylcellulose and a layer of an acrylic polymer and microcapsules produced thereby.

FIELD OF THE INVENTION

The present invention relates to the field of microencapsulation ofactive principles. A new process is described allowing to obtainpharmaceutical microcapsules with enhanced taste masking and an optimaldissolution profile.

STATE OF THE ART

Achieving an effective encapsulation of active principles is importantfor the preparation of a variety of compositions; when microparticles ofan active principle must be singly provided with an external coating,microencapsulation techniques are employed.

The microencapsulation process consists in coating small drug cores(microparticles) with a layer of polymer. The polymer layering may beachieved by different techniques; in particular the microencapsulationby phase separation (or coacervation), proved very reliable in obtainingcoated microparticles (M. Calanchi, “Taste Masking of oralformulations”, Pharmaceutical Manufacturing International, pp. 139-141,1996; L. Dobetti, S. De Luigi, “Developments in Microencapsulation”,Pharmaceutical Manufacturing and Packaging Sourcer, p. 39-40, Dec.1988).

The production of microcapsules differs from normal drug coatingtechniques in that singly coated, discrete microparticles must beobtained, e.g. in the order of 500 μm or less: to achieve this goal, theaggregation of the formed microcapsules must be avoided.

In the pharmaceutical field, microencapsulation of active principles isapplied in particular to prepare pharmaceutical multiparticulatecompositions such as syrups, permanent or temporary suspensions,chewable or fast melting tablets, etc. The microencapsulation is used inparticular to mask the taste of those drugs characterised by bitterness,throat-burning, saltiness and localised numbing of the tongue, etc.

Microencapsulation is also used to modulate the drug release profileafter administration. In principle, both taste masking andrelease-controlling properties are obtained by increasing the thicknessof the microcapsule wall. As a consequence, it is easy to preparetaste-masked, slow-release microcapsules, whereas it is more difficultto obtain taste-masked quick-release ones: the latter form isnevertheless very desired, in particular for those drugs with unpleasanttaste which, for pharmacokinetic and pharmacodynamic reasons, must bedelivered quickly in the stomach: one typical example is that ofantibiotic drugs (for example Penicillins, Cephalosporins, Carbapenem,Penems, Penams, Aminoglycosides, Macrolides, Ketolides, Tetracyclines,Quinolones, etc.) which are often endowed with an unacceptable taste:they require a strong taste-masking, but at the same time they must bedelivered and absorbed quickly in the stomach, so to ensure a quickonset of action and avoid disturbing the intestinal bacterial flora.

A second example is that of antinflammatory drugs or drugs for painrelief. Often this kind of drugs needs to be taste masked to avoidbitterness or throat burning, but at the same time a fast absorption ismandatory to assure a fast pain relief.

Third example is that of drugs characterised by a narrow absorptionwindow. These drugs require a fast release in the first part of thegastrointestinal tract to guarantee the proper bioavailability.

For the purpose of obtaining a good taste masking, the preferred andmost widely used sealing polymer is ethylcellulose. This polymer ischaracterised by an efficient sealing capacity and is easily layeredonto the drug microparticles; in addition it is an absolutely safeexcipient, free from toxicity problems. However ethylcellulose-coatedmicroparticles are not capable to associate, to the good taste masking,an elevated dissolution rate in the stomach. In order to overcome thisproblem, attempts have been made to reduce the thickness of themicrocapsule wall (i.e. using less encapsulating polymer); however thisis not a good solution because the taste-masking is no longer ensured bythe thinner coating. The use of coating polymers alternative toethylcellulose, having e.g. higher solubility in the stomach is equallyunsatisfactory: in fact, these polymers require much a thicker coatingto achieve the same level of taste masking of ethylcellulose; as aresult microcapsules with very low potency are obtained: they requirebulky dosage forms such as large tablets or capsules, thus quiteproblematic from the point of view of patient acceptability. Inaddition, with respect to ethylcellulose, polymers with highersolubility present problems of particle aggregation during the coatingprocess, with the result that small-size singly coated microparticlesare yet more difficult to obtain.

At present no microencapsulation process is available, capable toproduce small microcapsules, ensuring at the same time a good tastemasking, a fast onset of action, and a high potency.

SUMMARY OF THE INVENTION

The present application discloses a microencapsulation processcharacterised by coating drug cores with a first layer of ethylcelluloseand further coating the obtained microcapsules with a layer of anacrylic polymer. The obtained microcapsules show a high potency, anoptimal taste masking, and ensure a quick release in the stomach. Theinvention allows thus to produce superior pharmaceutical formulations,especially useful in the case of drugs with unpleasant taste inparticular drugs, which require an immediate delivery in the stomach,even if the administration in form of reconstitutable suspensions isrequired.

DESCRIPTION OF THE FIGURES

FIG. 1: Caffeine, microscope image of lot. B1, described in theexperimental part, showing an evident aggregation phenomena.

FIG. 2: Teophylline, particle size distribution of microcapsules ofinvention (lot. C2)

FIG. 3: Fluoxetine, microscope image of lot. C3, representing themicrocapsules of the invention.

FIG. 4: Caffeine, microscope image of lot. C1, representing themicrocapsules of the invention.

DETAILED DESCRIPTION OF THE INVENTION

A first objective of the present invention is a process for theproduction of microcapsules containing a drug, characterised by thefollowing steps:

-   a.—coating drug microparticles with a layer of ethylcellulose-   b.—further coating the product of a. with a layer of an acrylic    polymer

The present process is particularly suitable for those drugs which havean unpleasant taste and require quick delivery into the stomach;however, any drug available in microparticular form can be subjected tothe present process; for the purpose of the invention, the term “drug”includes also mixtures of two or more of them.

The step a. obtains singly coated microcapsules. The coating step a. canbe performed by microencapsulation techniques which, as such, arewell-known in the art. Among them, microencapsulation by phaseseparation (also known as microencapsulation by coacervation) ispreferred.

The known process of phase separation can be summarised in thefollowing, non limitative, step sequence: (i) dispersion: the creationof a two phase system in which a liquid phase (e.g. ethylcellulosesolution in cyclohexane) and a solid phase (drug particles) are presentsimultaneously; (ii) phase separation: thanks to the action of thecoacervation-inducing agent (e.g. an ethylene polymer like epolene) athird phase is formed. This phase called coacervate is a highlyconcentrated polymer solution in solvent which spreads onto the surfaceof the suspended drug cores. As a result, fluid droplets of coacervatecoalesce and enwrap the drug cores with a continuous layer of membrane(gel phase). The deposition of the polymeric membrane is promoted by areduction of the total free interfacial energy brought about by thedecrease of the coating material surface area during the coalescence ofthe liquid droplets; (iii) hardening: the fluid polymeric film ishardened by cooling down the suspension to room temperature; (iv)separation: microcapsules are separated from the liquid medium bysettling. The supernatant is then removed and the microcapsules can bewashed with fresh solvent to remove the residues of phase separationagent. Finally the microcapsules are filtered, dried and sifted.

Another known technique applicable to perform step a. is the fluidizedbed coating. In this case the ethylcellulose coating can be ensured byspraying onto pharmaceutical cores either an organic solution or anaqueous dispersion of the polymer. The choice is strictly dependent onthe chemical and physical characteristics of the cores to be coated.

If the next step b. is also performed by fluidized bed coating, theoverall process is particularly advantageous in that it can be performedin the same reactor by simply changing the coating solution when passingfrom step a. to b.

The product of step a. is an ethylcellulose microcapsule containing thedrug. Preferably the obtained microcapsule has a drug/ethylcelluloseweight ratio comprised between 1:1 and 30:1, more preferably between 3:1and 15:1. The drug/ethylcellulose weight ratio is herein referred as PR(phase ratio).

To apply the additional coating of acrylic polymer (step b.), it ispreferable to use a spray-coating technique: according to thisembodiment, the microcapsules obtained in step a. are suspended in afluidised bed and sprayed with a solution or suspension of the acrylicpolymer. Preferably, the solvent used to form this solution orsuspension is an acidic aqueous solvent, a hydroalcoholic solvent, anorganic solvent, or mixtures thereof. When a hydroalcoholic solution isused, it preferably comprises the following weight percentages ofcomponents, calculated with respect to the total weight of the solution:

-   acrylic polymer: 4-20%, preferably 7-20%-   alcohol (e.g. ethanol): 30-94%, preferably 40-75-   water: 0-40%, preferably 10-35%-   micronised inorganic material (e.g. talc): 2-20%, preferably 5-9%.

The acrylic polymer can be layered indifferently during one or morelayering steps: in the latter case a multilayered acrylic coating isobtained.

Advantageously, the product of step b. has an acrylic polymer contentcomprised between 5% and 40% by weight; an optimal range of this polymeris 10-25% The acrylic polymer used in step b. is chosen among acrylicpolymers for pharmaceutical use: they are well-known in pharmaceuticaltechnology, and can be indifferently linear, branched and/orcross-linked polymers of acrylic and/or methacrylic acid; the chosenpolymer must be soluble at acidic pH, (e.g. 1 g dissolves in 1N HCl);Representative, but not limitative examples of these polymers are theproducts of the class comprising Eudragit E (cationic copolymer based ondimethylaminoethyl methacrylate and neutral methacrylic esters).

A further object of the present invention are the microcapsules obtainedby the process above described. The process according to the presentinvention allows to obtain small taste-masked microcapsules (i.e. havinga weight median diameter comprised between 20-800 μm, preferably 100-400μm, with potency (i.e. mg drug/g of the end product of step b.)comprised between 400 and 950 mg/g, and capable to release at least 80%of the drug contained therein within 30 minutes, preferably in 10minutes in a simulated gastric fluid test or in acidic media. The highlevel of potency is a pharmaceutically advantageous feature which allowsto obtain, at constancy of drug content, smaller tablets or capsules,(i.e. containing lesser amounts of coating polymers) which are beingmore acceptable by the patient. The reduction in the amounts of coatingpolymers involves the further advantage that the present compositionscan dissolve in water without forming thickened viscous solutions aroundthe drug cores: this further eases the drug diffusion and theestablishing of a fast onset of action. The obtained microcapsulesfurther show the advantage of an improved suspendability in water, i.e.they do not form aggregates, do not float on the surface of a suspendingmedium, nor they adhere to side walls of a glass: therefore they do notrequire a separated wetting treatment with surfactants, such as insteadrequired in case of ethylcellulose microcapsules.

Moreover the obtained microcapsules show the capability of maintainingthe taste masking properties when suspended in neutral or basic aqueousmedia. The use of resuspended dosage form is often required for easinessand effectiveness of administration (e.g. dosage form as monodose sachetand dry powders for extemporaneous suspension).

The above described microcapsules, simultaneously ensuring elevatedtaste masking/elevated potency/elevated dissolution rate, are new andrepresent a further object of the present invention. These microcapsulescan be further processed, optionally in presence of suitablepharmaceutical excipients, into suitable pharmaceutical formulations,e.g. dry powders for extemporaneous suspensions, tablets, minitablets,microcapsule-containing capsules, monodose sachets, fast disintegratingtablets, syrups, etc.

The process and microcapsules of the invention can be used to taste-maska wide variety of active ingredients that have a bitter or non-bittertaste and that are desired to be released rapidly. Active ingredientsuseful with this invention include antibiotic and antibacterial agentssuch as ketolides; antiviral agents, analgesics, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants,antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatoryagents, antiemetics, antineoplastics, antiparkinsonism drugs,antipruritics, antipsychotics, antipyretics, antispasmodics, H2antagonists, cardiovascular drugs, antiarrhythmics, antihypertensives,ACE inhibitors, diuretics, vasodilators, hormones, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetics, psychostimulants, sedatives, antimigrane agentsantituberculosis agents and tranquilizers. Generally, the actives usedin conjunction with the present methodology are those which are bitteror otherwise unpleasant-tasting and thus in need of taste masking.

The present invention is now illustrated by reference to the followingexperimental examples which have no limiting function.

Experimental Part

Equipment

-   -   5 L microencapsulation reactor    -   pneumatic stirrer/propeller    -   break-water    -   thermostat    -   Tray dryer    -   Fluid bed        Materials    -   Caffeine    -   Teophyilline    -   Fluoxetine    -   Ethylcellulose    -   Polyethylene    -   Cyclohexane    -   Eudragit E    -   Micronised talc    -   Ethanol    -   Purified water        Process Description        Phase Separation

3000 g of cyclohexane were poured into a 5 L jacketed stainless steelreactor. Then, under a gentle stirring ensured by a helix, a fixedamount of drug, ethylcellulose and polyethylene were added.

The stirring rate was then increased to 500 rpm. The system was thenheated to 80° C. to cause the ethylcellulose solubilisation incyclohexane.

The final microcapsules were dried in an oven overnight at 40° C. andsifted by 500 μm screen.

Fluid Bed Coating

A fixed amount microcapsules obtained as described in the previousparagraph were loaded in a Glatt GPCG 1 fluid-bed equipped with 4″Wurster insert, plate type B, spraying nozzle 1.0 mm, and sprayed with acoating suspension having the following qualitative composition:

-   Eudragit® E100-   Micronised talc-   Ethanol-   Purified water

The second layer of coating suspension were subsequently applied. Thefinal product was sifted by 500 μm screen. The coating level obtainedwas calculated as microcapsules theoretical weight gain.

Residual cyclohexane, residual ethanol and residual polyethylene werewell within the acceptance limits for pharmaceuticals.

Analytical Methods

Dissolution Rate Method (i):

USP Paddle, 900 mL or 500 mL, HCl 0.1N or pH 1.2 buffer, 50 or 100 rpm,37° C. Samples were collected at fixed times, during, at least, 30minutes time period. Data at 10 minutes and 30 minutes are reported.

Taste Masking Evaluation (TM)

Obtained by sensorial judgement.

A fixed amount of microcapsules was evaluated as is or after suspensionin a appropriate aqueous media.

Particle Size Distribution (PSD)

Performed by sieve analysis using the automatic siever mod. OctagonDigital, equipped with sieves (Endecotts types).

D. Optical Microscopy (PSD)

Performed by a Ortolux microscope and a Zeiss Axioscopic 2 microscope.

Experimental Rationale

Three experimental sets were performed.

In the first set only the coating (i.e. ethylcellulose) was applied.

In the second set only the layer of the acrylic polymer was applied.

In the third set the drug microparticles were first coated with a layerof ethylcellulose and further with a layer of an acrylic polymer,according to what described in the present invention.

Results First Set Coating DRT DRT Potency Drug % w/w TM 10 min 30 minPSD % w/w Batch Caffeine 10 −− >80% >80% ++ 90 A1 Caffeine 30 ++   30%  54% ++ 70 A2 Theophylline 10 −− >80% >80% ++ 90 A3 Theophylline 15 −−  57% >80% ++ 85 A4 Theophylline 35 ++   19%   44% ++ 65 A5 Fluoxetine15 −− >80% >80% ++ 85 A6 Fluoxetine 20 −− >80% >80% ++ 80 A7 Fluoxetine30 +−   37%   65% ++ 70 A8Legenda:PSD (Particle Size Distribution)++: No significant aggregation−−: Significant aggregation+−: Improved but not acceptableTM (Taste Masking)++: Satisfactory−−: Not satisfactory+−: Improved but not acceptable

From the evaluation of the aforementioned results, it's evident that:

-   -   at low level of coating the dissolution rate is quite fast, but        the taste masking is not acceptable    -   at higher level of coating the taste masking properties        significantly improve, but the release profile is too slow and        therefore not acceptable. Moreover the potency decreases        dramatically    -   in some cases, even using higher levels of coating (with a        significant decrease of the dissolution rate), the taste masking        is not acceptable. This is probably related to a higher surface        area of the drug used.

the application of ethylcellulose, even at high percentage, leads toacceptable particle size distribution Second Set Coating DRT DRT PotencyDrug % w/w TM 10 min 30 min PSD % w/w Batch Caffeine 10 −− n.a. n.a. −−90 B1 Theophylline 25 −− >80% >80% +− 75 B2 Theophylline 40 −− >80% >80%+− 60 B3 Fluoxetine 30 −− >80% >80% −− 70 B4 Fluoxetine 40 −− >80% >80%−− 60 B5n.a.: not available. DRT was not performed due to dramatic agglomerationphenomenaLegenda:PSD (Particle Size Distribution)++: No significant aggregation−−: Significant aggregation+−: Improved but not acceptableTM (Taste Masking)++: Satisfactory−−: Not satisfactory+−: Improved but not acceptable

From the evaluation of the aforementioned results, it's evident that:

-   -   the application of the acrylic polymer, even at high percentage,        doesn't affect significantly the release in simulated gastric        fluid, but is not able to assure the required taste masking    -   even applying a low level of acrylic polymer, the particle size        distribution resulted not acceptable due to agglomeration        phenomena.

In order to overcome this drawback, the coating of batches B2 and B3 wasperformed using a very low spraying rate, leading to a time consumingprocess, not economically compatible with an industrial application ofthis technology. Despite using this condition, the particle sizedistribution was not considered completely satisfactory due to aresidual aggregation. Anyway the taste masking properties were notsatisfactory. Third Set I Coating II Coating DRT DRT Potency Drug % w/w% w/w TM 10 min 30 min PSD % w/w Batch Caffeine 7.5 25 ++ >80%   >80% ++67.5 C1 Theophylline 11.3 25 ++ 54% >80% ++ 63.7 C2 Fluoxetine 24.2 15++ 76% >80% ++ 60.8 C3Legenda:PSD (Particle Size Distribution)++: No significant aggregation−−: Significant aggregation+−: Improved but not acceptableTM (Taste Masking)++: Satisfactory−−: Not satisfactory+−: Improved but not acceptable

From the evaluation of the aforementioned results, it's evident that:

-   -   The application of the two layers leads to microcapsules able to        properly mask the taste, even when suspended in a liquid media,        and also ensuring a fast release and avoiding significant        microcapsule aggregation.    -   Moreover the overall coating amount is relatively low, so        ensuring the possibility to obtain suitable potency.

1. A process for the production of microcapsules containing a drug,comprising the following steps: a. coating drug microparticles with alayer of ethylcellulose b. further coating the product of a. with alayer of an acrylic polymer.
 2. A process according to claim 1, wherethe coating in step a. is applied by phase separation microencapsulationor by fluidized bed coating.
 3. A process according to claim 1, whereinthe coating in step b. is applied by spraying a solution of suspensionof acrylic polymer onto the particles obtained in a., suspended in afluidized bed.
 4. A process according to claim 3, wherein said solutionor suspension is a hydroalcoholic solution, comprising the followingweight percentages of components, calculated with respect to the totalweight of the solution: acrylic polymer: 4-20% alcohol: 30-94% water:0-40% micronised inorganic material: 2-20%
 5. A process according toclaim 3, wherein said hydroalcoholic solution or suspension comprisesthe following weight percentages of components, calculated with respectto the total weight of the solution: acrylic polymer: 7-20% alcohol:40-75% water: 10-35% micronised inorganic material: 5-9%
 6. A processaccording to claim 4, wherein said alcohol is ethanol, and saidinorganic material is talc.
 7. A process according to claim 1, whereinthe product of step a. has a drug/ethylcellulose weight ratio (phaseratio) comprised between 1:1 and 30:1, and the product of step b. has anacrylic polymer content comprised between 5% and 40% by weight.
 8. Aprocess according to claim 1, wherein the product of step a. has adrug/ethylcellulose weight ratio (phase ratio) comprised between 3:1 and15:1, and the product of step b. has an acrylic polymer contentcomprised between 10% and 25% by weight.
 9. A process according to claim1, wherein the taste-masked microcapsules obtained in step b. have aweight median diameter comprised between 20 and 800 μm, drug potencycomprised between 400 and 950 mg/g, and are capable of releasing atleast 80% of the drug contained therein within 30 minutes in a aqueousacidic media.
 10. Microcapsules containing a drug, obtainable by theprocess described in claim
 1. 11. Microcapsules according to claim 10,formulated in a pharmaceutical administrable form.
 12. Microcapsulesaccording to claim 11, wherein said pharmaceutical administrable form ischosen from dry powders for extemporaneous suspensions, tablets,minitablets, microcapsule-containing capsules, monodose sachets, fastdisintegrating tables, syrups.
 13. Microcapsules according to claim 10,wherein said drug is chosen from penicillins, cephalosporins,carbapenem, penems, penams, aminoglycosides, macrolides, ketolides,tetracyclines, quinolones.
 14. A process according to claim 9 whereinthe taste-masked microcapsules obtained in step b. have a weight mediandiameter comprised between 100 and 400 μM and a drug potency comprisedbetween 400 and 950 mg/g.